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Original Studies |
Department of Pediatrics, Oregon Health Sciences University (V.H., A.L.B., R.G.R.), Portland, Oregon 97201; and the Geriatric Research, Education, and Clinical Center, Veterans Affairs Health Care System Puget Sound (C.T.-S., S.R.P.), Tacoma, Washington 98493
Address all correspondence and requests for reprints to: Dr. Vivian Hwa, Department of Pediatrics, NRC5, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In biological fluids, IGFs are normally sequestered by IGF-binding proteins (IGFBPs), of which there are six, designated IGFBP-1 to -6 (7, 8, 9, 10). As IGFs have higher binding affinities for IGFBPs than for the IGF-IR, IGFBPs are important in the modulation of IGF biological activity. The effect can be an inhibition (11, 12) or an enhancement of IGF-IGF-IR interactions (13). In addition to these IGF-dependent actions of IGFBPs, IGFBPs have important biological actions independent of their abilities to bind IGFs. The IGF-independent effects of IGFBPs can be antiproliferative (14, 15) or growth stimulatory (16).
The IGFBP family has recently been expanded to include a group of additional cysteine-rich proteins that are involved in regulating cell growth (17, 18, 19). These IGFBP-related proteins (IGFBP-rPs) share structural features with the conventional IGFBPs, IGFBP-1 to -6 (20). For the conventional IGFBPs, a striking shared feature is the conservation of critical cysteines, clustered at the N-terminus third (12 cysteines) and the C-terminus third (6 cysteines) of the proteins (7). It has been hypothesized that the N- and C-termini are independent domains that together are responsible for the high affinity IGF binding characteristic of IGFBPs (21). The IGFBP-rPs contain the N-terminal domain of the IGFBPs, but their C-terminal domains have clearly diverged (17, 20, 22, 23). In addition to structural similarities, there are functional similarities between the IGFBP-rPs and IGFBPs. Two of the IGFBP-rPs, IGFBP-rP1, Mac25 (22), and IGFBP-rP2, CTGF (23), are able to bind IGF-I, although with a 20- to 100-fold reduced affinity compared to that of IGFBP-3 (18, 19). The existence of cysteine-rich proteins with conserved N-terminus domains and demonstrable abilities to bind IGFs, albeit with lower affinities than the conventional IGFBPs, has led to the proposal of an IGFBP superfamily, subdivided into high affinity IGF binders (IGFBP-1 to -6) and low affinity IGF binders (IGFBP-rPs) (19). The ability of these low affinity IGF binders to modulate IGF bioactivity in vivo is not known, and only scant data are available on their IGF-independent actions.
The conventional IGFBPs in the prostate have been well characterized, whereas virtually nothing is known regarding prostate IGFBP-rPs. IGFBP-2 to -6 have been detected in stromal and epithelial prostate cells as well as in prostatic epithelial cell lines (1, 24, 25, 26, 27, 28, 29, 30). The pattern of detectable IGFBPs is altered in malignant prostatic cells (31, 32). The significance of changes in IGFBP levels in malignancy has yet to be determined, but probably includes altered modulation of IGF bioactivity (4, 33, 34) as well as biological effects independent of IGFs (35, 36, 37).
Of the IGFBP-rPs, IGFBP-rP1 (Mac25) messenger ribonucleic acid (mRNA) has been detected in the prostate (18). The complementary DNA (cDNA) for Mac25 (22) was originally cloned from leptomeningial cells by differential display. The mac25 cDNA was found to be preferentially expressed in normal leptomeningial and mammary epithelial cells compared to their counterpart tumor cells (22, 38) and to be up-regulated in senescent human mammary epithelial cells (38). These results suggested that mac25 played a role in growth-regulating pathways that are abrogated in meningiomas and breast carcinoma. The same apparent protein and cDNA have been isolated from human bladder carcinoma cells [tumor-derived adhesion factor (TAF)] (39) and from human diploid fibroblast cells [prostacyclin-stimulating factor (PSF)] (40). Functionally, TAF at high concentrations (>1 µg/mL) appears to promote cell adhesion of cancer cells and to stimulate growth of mouse fibroblasts (41, 42); PSF was shown to stimulate prostacyclin synthesis in endothelial cells. Oh et al. (18) synthesized that the Mac25 protein (which they redesignated IGFBP-7) in a baculovirus system and demonstrated that it can bind IGF as well as insulin; similar results were obtained by Yamanka et al., using purified TAF protein (21). A Northern blot showing tissue distribution of IGFBP-rP1 (Mac25/TAF/PSF/IGFBP-7) mRNA indicated an abundance of the mRNA in normal prostate and a distinct decrease of mRNA levels in prostate cancer cells (18). This result supports the hypothesis that IGFBP-rP1 is involved in regulating cell growth.
As IGFBP-rP1 is potentially important in the regulation of normal prostate cell growth, we studied the mRNA and protein expression of IGFBP-rP1 in both normal and malignant prostate cells and demonstrated that in immortalized nonmalignant epithelial cells, P69 cells (43), IGFBP-rP1 expression is regulated by IGF-I, transforming growth factor-ß (TGFß), and retinoic acid (RA).
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Materials and Methods |
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F-12 nutrient mixture (Ham’s) powder, epidermal growth factor (EGF), dexamethasone, all-trans-retinoic acid, and the additive ITS (insulin, transferrin, selenium) were purchased from Sigma Chemical Co. (St. Louis, MO). RPMI 1640, HEPES, fungizone, and gentamicin were obtained from Life Technologies (Grand Island, NY). IGF-I was a gift from Eli Lilly & Co. (Indianapolis, IN). TGFß1 was purchased from Austral Biologicals (San Ramon, CA). Bovine pituitary extract was obtained from Upstate Biotechnology, Inc. (Lake Placid, NY). FBS was obtained from HyClone Laboratories, Inc. (Logan, UT). Nitrocellulose and electrophoresis reagents were purchased from Bio-Rad Laboratories, Inc. (Richmond, CA); nylon membranes (GeneScreen) were obtained from New England Nuclear (Boston, MA). Horseradish peroxidase-linked donkey antirabbit IgG and enhanced chemiluminescence detection reagents were purchased from Amersham (Arlington Heights, IL). Polyclonal antibody against IGFBP-rP1 (IGFBP-7) (18) was generated in rabbits (44).
In situ hybridization
Prostate tissues were obtained from patients undergoing radical prostatectomies and processed for in situ hybridization as described previously (26, 27). The cDNA used for in situ hybridization was a 0.88-kb SspI-XbaI IGFBP-rP1 cDNA fragment cloned in pBluescript SK+ (Stratagene, La Jolla, CA). Antisense mRNA was prepared from the linearized plasmid from the T7 promoter. Specificity of the hybridization was determined by the use of duplicate slides that were hybridized with 35S-labeled RNA probe and a 100-fold excess of unlabeled RNA. Specificity of this probe is also indicated by hybridization to a single 1.1-kb mRNA species on Northern blots of total cytoplasmic RNA from primary cultures of human prostate epithelial cells and prostate stromal cells.
Cell culture
Biopsies of prostate tissue from the central and peripheral zones were obtained during radical prostatectomies. The tissue samples were digested, and the epithelial and stromal cells were separated (28). The primary epithelial cells are composed of predominantly basal epithelial cells; however, a central portion of the culture reacts with an antibody to prostate-specific antigen as well as to an antibody to cytokeratin-8, suggesting a luminal component. Primary epithelial cells were maintained in HEPES/F-12 medium supplemented with 10 ng/mL EGF, 0.1 µmol/L dexamethasone, 5 ng/mL selenium, bovine pituitary extract, fungizone, and gentamicin, whereas stromal cells were cultured in HEPES/F-12 medium supplemented with fungizone, gentamicin, and 5% FBS. Both lines were maintained at 37 C under 5% CO2.
The derivation of the P69 and M12 cell lines has been previously described (43, 45). P69 cells are simian virus 40 T antigen-immortalized, normal human prostate epithelial cells that are poorly tumorigenic. M12 cells are a metastatic subline of P69 cells generated by serial passage through athymic mice. Both cell lines were cultured in RPMI 1640 medium supplemented with 10 ng/mL EGF, 0.1 µmol/L dexamethasone, 5 µg/mL insulin, 5 µg/mL transferrin, 5 ng/mL selenium, fungizone, and gentamicin at 37 C under 5% CO2.
All cells used in these experiments were mycoplasma free as determined by the Mycoplasma PCR Primer Set (Stratagene).
Growth factor treatment studies
All cell lines mentioned above were grown to 80% confluence in 100-mm tissue culture dished and treated with various doses of IGF-I (0–100 ng/mL), RA (0, 10-7, 10-9, 10-11, and 10-13 mol/L), or TGFß (0, 1, and 5 ng/mL) in RPMI 1640 supplemented with 5 µg/mL transferrin and 5 ng/mL selenium. After 24 h of treatment, medium and total cytoplasmic RNA were collected for Western immunoblots (see Western immunoblot analysis) and Northern blots (see RNA analysis), respectively. All experiments were repeated in triplicate.
Western immunoblot analysis of IGFBP-rP1 expression
Media taken from both treated and untreated (control) cells were normalized based on cell counts and concentrated by filtration through nitrocellulose. After concentration, proteins were redissolved in 23 µL denaturing SDS sample buffer [0.5 mol/L Tris (pH 6.8), 1% SDS, 10% glycerol, and 8 mol/L urea] and boiled for 10 min. For studies specifically involving P69 cells, conditioned media (CM) were not concentrated, as IGFBP-rP1 was readily detectable. Samples were electrophoresed on 12% SDS-polyacrylamide gels, then electroblotted onto nitrocellulose. Western blots were incubated with IGFBP-rP1 antiserum at a 1:3000 dilution in Tris-buffered saline-Tween-20 (0.1%) overnight at 4 C. Blots were washed with Tris-buffered saline-Tween-20 and then incubated for 1 h at 22 C with a 1:2500 dilution of horseradish peroxidase-linked antirabbit IgG secondary antibody. IGFBP-rP1 was detected with ECL chemiluminescence reagents according to the manufacturer’s protocol.
RNA analysis
Total cytoplasmic RNA was isolated from cells using RNeasy
(Qiagen, Inc., Chatsworth, CA). Eight to 10 µg of each RNA
preparation were electrophoresed on a 1.2% agarose-2.2 mol/L
formaldehyde gel, transferred overnight onto a nylon membrane
(GeneScreen, DuPont, Wilmington, DE) using 10 x SSC (standard
saline citrate) as the transfer solution, and cross-linked to the
membrane by UV irradiation in a Stratalinker 1800
(Stratagene). The Northern blots were then probed with a
660-bp EcoRI-SmaI fragment of the IGFBP-rP1 cDNA
(18), which was radiolabeled (1 x 109 dpm/µg) with
[
-32P]deoxy-CTP (New England Nuclear-DuPont; SA, 3000
Ci/mmol) using a random priming kit (Prime-a-Gene, Promega Corp., Madison, WI). Northern blots were hybridized overnight at
42 C in 50% formamide, 5 x SSC, 10 x Denhardt’s solution,
1% SDS, and 100 µg/mL sheared denatured herring sperm DNA; in some
cases, hybridization was performed using Rapid-Hyb buffer (Amersham)
and according to the manufacturer’s instructions. Blots were then
washed for 30 min in 2 x SSC at room temperature, for 30 min in
2 x SSC-0.1% SDS at room temperature, and stringently washed at
55 C in 0.2 x SSC-0.1% SDS for 10–20 min. Blots were exposed to
Kodak XAR film or to Kodak Biomax MS film (Eastman Kodak Co., Rochester, NY) for 1–4 days at -70 C using one
intensifying screen,. Membranes were then stripped in SDS for 10–30
min and reprobed with actin or 18S, which acted as a loading control
for the RNA samples. An image analyzer equipped with MCID version 4.2
software (Imaging Research, Inc., St. Catherines, Canada)
was used to quantify the resulting bands.
In addition to the blots prepared from the growth factor studies, Northern blots prepared with either polyadenylated RNA or total RNA isolated from microdissections of normal and tumorigenic prostate tissue were obtained from Dr. Peter Nelson (University of Washington, Seattle, WA). These blots were probed, incubated, washed, and analyzed as described above.
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Results |
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In situ hybridization experiments using
35S-labeled antisense cDNA to IGFBP-rP1 were performed on
prostate tissue sections, normal and malignant, to determine the
expression of IGFBP-rP1. Normal tissue from 27 prostate glands and
lymph nodes from 2 men in which prostate cancer had metastasized were
examined, and representatives are shown in Fig. 1
. In normal prostate tissue, intense
labeling of IGFBP-rP1 message was detected in stromal areas as well as
in the glandular epithelium that surrounds the lumin (Fig. 1, A and B).
Note that there is a clear increase in grain intensity from luminal
epithelial cells to basal epithelial cells, suggesting that IGFBP-rP1
mRNA is produced by both luminal and basal epithelial cells. In
contrast, malignant prostate tissues demonstrate a dramatic loss in
detectable IGFBP-rP1 mRNA, as shown in tissue sections of prostate
cancer metastasized to a lymph node (Fig. 1, C and D). Note that the
lymph node itself produces minimal IGFBP-rP1 mRNA. In the metastasized
tissue, the prominent prostate epithelial cells appear to express very
little IGFBP-rP1, although IGFBP-rP1 mRNA was still readily detectable
in stromal areas. The labeling of IGFBP-rP1 mRNA was specific, as
unlabeled IGFBP-rP1 cDNA (100-fold excess) reduced signals to
background levels (data not shown). The marked decrease in IGFBP-rP1
mRNA expression in malignant prostate cells compared to normal cells
was further supported by Northern blots of mRNA extracted from
microdissections of human prostate epithelial cells (Fig. 2). There was a progressive loss of
detectable IGFBP-rP1 mRNA going from normal cells to malignant
prostate epithelial cells.
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Although IGFBP-rP1 mRNA is present and readily detectable in
prostate, it is not clear whether IGFBP-rP1 protein is transcribed from
these transcripts. The rabbit polyclonal antibody generated against
baculovirus-purified IGFBP-rP1 (anti-IGFBP-7) (44) has been employed
for immunoblotting and immunoprecipitations to demonstrate the presence
of IGFBP-rP1 protein in biological fluids and CM of various cell lines
(44). Therefore, to further characterize IGFBP-rP1 mRNA and protein in
the prostate, IGFBP-rP1 expression in primary cultures of normal
epithelial and stromal prostate cells as well as in simian virus 40
T-antigen transformed epithelial cells, P69 (43), and its tumorigenic
and metastatic subline, M12 (45), were analyzed. Northern blots of
total RNA extracted from these cells indicate detectable IGFBP-rP1 mRNA
of approximately 1.1 kb in all cell lines, with the most abundant
message detected in primary stromal cells (Fig. 3B) and the least abundant in M12
cells.
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). The size of the protein detected is
consistent with the size of IGFBP-rP1 that was detected in biological
fluids and in CM from the breast cancer cell line Hs578T (44). The
concentrations of IGFBP-rP1 detected in the CM from the prostate cell
lines suggest that M12 expresses the least amount of IGFBP-rP1, with
stromal cells expressing the highest concentrations. The IGFBP-rP1
protein concentration detected in CM from stromal cells reflects the
high level of IGFBP-rP1 mRNA detected. Expression of IGFBP-rP1 mRNA and protein was also investigated in the well established prostate cancer cell lines, PC-3, LNCaP, and DU145 cells. In serum-free medium, IGFBP-rP1 mRNA was detectable by Northern blots, but IGFBP-rP1 protein was not detectable in CM by either immunoblots or immunoprecipitation of CM from 35S-Met-labeled cells (data not shown).
IGFBP-rP1 expression is regulated in P69 cells
In normal mammary epithelial cells, mac25 (IGFBP-rP1) is regulated by RA (38). To determine whether IGFBP-rP1 is regulated in prostate cells, we investigated the effects of various growth factors (IGF-I, TGFß, and RA) on expression of IGFBP-rP1 in P69 cells and its subline, M12 cells. P69 cells are responsive to the growth stimulatory effects of IGFs, whereas M12 cells are considerably less responsive, probably due to an 80% decrease in IGF-I receptors per cell compared to those in P69 cells (46). Epithelial cells are known to be inhibited by growth factors such as TGFß and RA. Hence, examining the effects of these three factors on IGFBP-rP1 expression might provide clues for the role(s) of IGFBP-rP1 in prostate cell proliferation.
IGFBP-rP1 in P69 cells is regulated by all three growth factors tested
(Figs. 4-6).
In contrast, IGFBP-rP1 in M12 was not regulated at the concentrations
of growth factors tested (data not shown). IGF-I up-regulated IGFBP-rP1
in P69 cells in a dose-dependent manner at both mRNA and protein levels
(Fig. 4). IGFBP-rP1 protein showed increases of 3.5-fold at 10 ng/mL
and 5-fold at 100 ng/mL (Fig. 4A), and mRNA levels were increased 2.5-
and 5-fold, respectively, compared to those in untreated cells. Western
ligand blot of CM also showed that at these concentrations of IGF-I,
some of the IGFBPs detectable in P69 cells, in particular IGFBP-2, -3,
and -4 (46), were also significantly increased (data not shown).
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). Western ligand blots of the
same CM indicated that RA, even at 1 µmol/L (data not shown), did not
change the levels of the other IGFBPs in P69 cells. TGFß up-regulated
IGFBP-rP1 mRNA and protein dose dependently and significantly, although
the increases were also modest (Fig. 6). IGFBP-rP1 mRNA was increased
2.5-fold in cells treated with 5 ng/mL TGFß, and IGFBP-rP1 protein
was increased 2-fold. Of the IGFBPs, IGFBP-3 protein was up-regulated
by TGFß concomitantly with IGFBP-rP1 (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The decrease in IGFBP-rP1 expression in malignant prostate cells is consistent with the hypothesis that IGFBP-rP1 may have tumor-suppressive activity, although the specific role(s) of IGFBP-rP1 has yet to be determined. A clue to one role that IGFBP-rP1 may play in cell growth came from our studies using M12 cells (45), a tumorigenic subline of P69 cells. In these studies, IGFBP-rP1 appears to have proapoptotic activities, as overexpression of IGFBP-rP1, generated by stable transfection of M12 cells with IGFBP-rP1 cDNA, dramatically decreased the growth rate of the transfected cells and concomitantly increased the sensitivity of M12 cells to apoptotic agents such as 6-hydroxyurea (C. Tomasini-Sprenger, submitted). Thus, it is possible that in normal prostate cells, IGFBP-rP1 regulates cell growth, directly or indirectly, through apoptotic pathways, and loss of IGFBP-rP1 could, therefore, enhance abnormal cell growth.
IGFBP-rP1 mRNA was detected in all cell lines tested. However, IGFBP-rP1 protein was detectable in CM from primary cultures of prostate stromal and epithelial cells, P69 and M12, but not in CM from PC-3, DU145, or LNCaP prostate cancer cell lines. The inability to detect IGFBP-rP1 protein in CM from cancer cells does not rule out the possibility that a very low concentration of IGFBP-rP1 is present in the CM. These results are consistent with decreased expression of IGFBP-rP1 in epithelial cells of malignant prostate. Further evidence that decreased IGFBP-rP1 expression occurs with tumorigenesis can be found in the reduced expression of IGFBP-rP1 mRNA and protein between the P69 and M12 cells. The P69 cells are poorly tumorigenic, whereas the subline M12 is highly tumorigenic and metastatic (43, 45, 46). P69 cells express much higher levels of IGFBP-rP1 mRNA and protein than M12 cells. As these cells are linearly related, this is evidence for a decrease in IGFBP-rP1 expression during transformation.
Interestingly, primary cultures of stromal cells expressed extraordinary quantities of IGFBP-rP1 mRNA and protein. In situ hybridization experiments also indicate high levels of IGFBP-rP1 mRNA present in stromal cells in both normal and malignant prostate tissue. The reason for the high expression of IGFBP-rP1 by stromal cells has yet to be determined, but one possibility is that the secreted IGFBP-rP1 protein from stromal cells may act as a paracrine regulator of normal epithelial cell growth.
Regulation of IGFBP-rP1 expression by IGF-I, RA, and TGFß was also examined in all cell lines. Only in P69 cells was IGFBP-rP1 regulation detectable; there was no obvious regulation of IGFBP-rP1 protein in normal prostate epithelial or stromal cells, M12 cells, or from prostate cancer cell lines, PC-3, DU145, and LNCaP (data not shown). Consistent with observations reported for normal mammary epithelial cells (38), IGFBP-rP1 was also modestly up-regulated 2-fold by RA at both the mRNA and protein levels in the immortalized epithelial P69 cells, although the same regulation was not seen in primary cultures of epithelial cells. It should be noted that in normal mammary epithelial cells, IGFBP-rP1 regulation was only detectable in early and midpassages of the cells, and regulation was lost upon further passaging of the cells. This suggests a narrow window of time in which RA appears to be capable of regulating IGFBP-rP1 expression and could be easily missed.
IGFBP-rP1 expression in P69 cells is also up-regulated by TGFß1. Both RA and TGFß1 are known inhibitors of epithelial cell growth. In breast cancer cells, it has been clearly demonstrated that the growth inhibitory action of TGFß1 and RA is mediated in part by the up-regulation of IGFBP-3 protein (47, 48), which has antiproliferative activity (15, 35). It is, therefore, conceivable that in P69 cells, the actions of TGFß1 and RA may be partially mediated by IGFBP-rP1. TGFß1 also specifically up-regulated IGFBP-3 in P69 cells; the antiproliferative function of IGFBP-3 in these cells cannot, therefore, be excluded. The roles of IGFBP-rP1 and IGFBP-3 in mediating TGFß1 and RA actions are currently under investigation. Interestingly, IGF-I, which is mitogenic for P69 cell growth (46), up-regulates IGFBP-rP1 as well as the other IGFBPs detectable in P69 cells. It is not clear what roles IGFBPs and IGFBP-rP1 play in IGF-I-stimulated growth.
In this report we have characterized the expression of IGFBP-rP1, a member of the IGFBP superfamily (20), in prostate cells. The observations that IGFBP-rP1 expression is significantly diminished with tumorigenesis and that expression is regulated in nonmalignant epithelial cells indicate the importance of IGFBP-rP1 in normal prostatic cell growth. The findings further support a potential antiproliferative effect of IGFBP-rP1 in the prostate, either by proapoptotic means or other mechanisms.
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Footnotes |
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Received June 15, 1998.
Revised September 1, 1998.
Accepted September 8, 1998.
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